GME Research Review

GME Research Review is a monthly newsletter edited by Rajnish Mago, MD, Associate Professor of Psychiatry at Thomas Jefferson University, author of The Latest Antidepressants and Side Effects of Psychiatric Medications: Prevention, Assessment, and Management. Dr. Mago selects, summarizes, and provides a clinical commentary on the latest published research in psychiatry.

We are always carefully evaluating which research papers to discuss in GME Research Review. Have come across a research paper published in the last 6 months that you thought is clinically relevant? Do you want me to analyze it for you and for the benefit of others? Please email me the citation at [email protected]

Vortioxetine (Brintellix) is a newly introduced antidepressant. The main area in which there is some suggestion that vortioxetine may differentiate itself from other antidepressants is in reduction in cognitive dysfunction.

Background

There is some pre-clinical and clinical research to suggest the possibility that vortioxetine may be particularly helpful for the cognitive dysfunction that frequently accompanies major depressive disorder.

But treatment of depression with any efficacious antidepressant leads to improvement in cognitive dysfunction associated with major depression. Therefore, attempts are being to assess whether vortioxetine also improves cognitive dysfunction independently of improvement in depression.

Methods

This was a randomized, double-blind, placebo-controlled study of vortioxetine (10 to 20 mg/day), duloxetine (60 mg/day), or placebo.

Vortioxetine was started at 10 mg/day with the option to increase to 20 mg/day if needed and tolerated. However, duloxetine was given at 60 mg/day from day 1 with no option to modify the dose.

602 patients were randomized in the study.

Persons included in the study:

1. Were adults 18 to 65 years

2. Had a diagnosis of major depressive disorder (MDD)

3. Said that they had cognitive dysfunction such as difficulty concentrating, slow thinking, and difficulty in learning new things or remembering things.

4. Had a score of < 70 on the Digit Symbol Substitution Test–number of correct entries (DSST performance). That is, they had at least some impairment on the main measure of cognitive dysfunction used in this study.

5. Did not have a history of lack of response to duloxetine. Good.

The primary efficacy end point was the number of correct symbols on the Digit Symbol Substitution Test (DSST). This measure evaluates several cognitive functions including executive functioning, processing speed, attention, spatial perception, and visual scanning.

Results

Mean dose of vortioxetine during the study was 16.0 mg/day.

Both vortioxetine and duloxetine were statistically significantly more efficacious than placebo in reducing the severity of depression as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Clinical Global Impression-Improvement scale (CGI-I).

Vortioxetine was also statistically significantly more efficacious than placebo in reducing cognitive dysfunction as measured by:

1. The Digit Symbol Substitution Test (DSST)

2. The patient-rated Perceived Deficits Questionnaire (PDQ)

3. The University of San Diego Performance-based Skills Assessment (UPSA)

Duloxetine was not statistically significantly better than placebo on the Digit Symbol Substitution Test (DSST; the primary outcome measure) or on the University of San Diego Performance-based Skills Assessment (UPSA). However, duloxetine did reduce cognitive dysfunction statistically significantly more than placebo on the patient-rated Perceived Deficits Questionnaire (PDQ).

On one questionnaire, the Cognitive and Physical Functioning Questionnaire (CPFQ), vortioxetine was not statistically significantly better than placebo (though there was a statistical “trend:” p value was 0.086). However, in the subgroup of patients who started out with more than minimal dysfunction on the CPFQ, vortioxetine did improve functioning more than placebo. Duloxetine was statistically significantly better than placebo in both the entire group of patients and the subgroup mentioned above. (These are the vagaries of statistical testing!)

In order to try to assess the extent to which the reduction in cognitive dysfunction in patients on vortioxetine was due to a direct effect versus due to reduction in depression, a statistical analysis approach called “path analysis” was conducted. (For those with some knowledge of statistics, this is a form of multiple regression.)

The path analysis suggested that the 76% and 49%, respectively, of the reduction in cognitive dysfunction with vortioxetine and with duloxetine was due to a direct effect.

Conclusions

In adults with major depressive disorder who self-reported cognitive dysfunction, vortioxetine was statistically significantly better than placebo in improving depression, cognitive function, and functioning.

Clinical Commentary

The reader may be wondering what to conclude about what might be the most important question: was vortioxetine better than duloxetine in improving cognitive dysfunction? In this regard, here are the key facts:

1. There was no statistically significant difference between vortioxetine and duloxetine on the pre-specified primary outcome measure (DSST performance score). This is most important comparison.

2. Admittedly, this study was not powered (i.e., did not have enough patients in each group) to compare vortioxetine to duloxetine with statistical confidence.

3. Vortioxetine was statistically significantly better than duloxetine on the University of San Diego Performance-based Skills Assessment (UPSA).

Overall, this study adds to the literature supporting a role for vortioxetine in reducing cognitive dysfunction associated with major depressive disorder. This is supported by two other double blind placebo controlled trials showing improvement in cognition in MDD. Based on this data Takeda and Lundbeck have filed a sNDA with the FDA for a label change similar to the label in Europe.

This study aimed to assess the efficacy, safety, and tolerability of brexpiprazole versus placebo in adults with acute schizophrenia.

Methods

This was a multicenter, randomized, double-blind, placebo-controlled study.

Patients with schizophrenia experiencing an acute exacerbation were enrolled.

636 subjects were randomly assigned to 6 weeks of treatment with brexpiprazole 0.25 mg/day, 2 mg/day, or 4 mg/day, or with placebo.

Results

At baseline, subjects were markedly (i.e., more than moderately) ill.

At week 6, patients who received brexpiprazole 2 mg/day or 4 mg/day had statistically significantly greater improvement than those who received placebo based on both the Positive and Negative Symptom Scale (PANSS) and the Clinical Global Impressions-Severity scale.

As expected, the 0.25 mg/day dose was not statistically significantly more efficacious than placebo.

Based on a 50% or greater reduction in the PANSS score, the percentages of responders were 30% with placebo, 47% with brexpiprazole 2 mg/day, and 44% with brexpiprazole 4 mg/day. Thus, the drug-placebo difference was 17% and 14%, respectively, which is above the 10% difference that is considered the minimum required for a clinically meaningful difference. Slightly greater drug-placebo differences were found based on a 30% or greater improvement that was the prespecified percentage key secondary efficacy measure.

There was no statistically significant difference between brexpiprazole and placebo on the change from baseline in scores on the Barnes Akathisia Rating Scale, Simpson-Angus Scale, or Abnormal Involuntary Movement Scale.

The only adverse event that occurred in at least 5% of patients on either 2 mg/day or 4 mg/day of brexpiprazole and at least twice as often as on placebo was:

Akathisia -- 2% on placebo, 4% on brexpiprazole 2 mg/day, and 7% on brexiprazole 4 mg/day. No patient discontinued treatment due to akathisia.

Other adverse effects that occurred with brexpiprazole (2 mg/day or 4 mg/day) at least twice as often as with placebo were:

Increased body weight was spontaneously reported as an adverse event by 2% of patients on placebo, 3% of those on brexpiprazole 2 mg/day, and 4% of those on brexpiprazole 4 mg/day.

In clinical trials, an increase in body weight of 7% or more is considered to be significant weight gain. Such weight gain was seen in 4% of patients on placebo and 9% of patients on either 2 mg/day or 4 mg/day of brexpiprazole.

There were no clinically or statistically significant changes from baseline in lipid and glucose levels or in extrapyramidal symptom ratings.

Conclusions

Brexpiprazole at dosages of either 2 mg/day or 4 mg/day was efficacious for the treatment of acute exacerbation of schizophrenia.

Clinical Commentary

Brexpiprazole showed a both statistically and clinically significant improvement compared to placebo, thus demonstrating that it is efficacious for treatment of acute exacerbations of schizophrenia.

Head-to-head studies should be conducted in order to better understand how it compares to other available second-generation (“atypical”) antipsychotics, particularly aripiprazole.

A key tenet of science is reproducibility, which is why the FDA requires at least two separate randomized, controlled trials that show the efficacy of the drug.

Background

This study aimed to evaluate the efficacy, safety and tolerability of brexpiprazole versus placebo in adults with acute schizophrenia.

Methods

This was a multicenter, randomized, double-blind, placebo-controlled study.

Patients with acute exacerbation of schizophrenia were enrolled.

Subjects were randomized to 6 weeks of treatment with brexpiprazole 1, 2 or 4 mg/day, or placebo.

Results

Brexpiprazole 4 mg/day showed statistically significant improvement versus placebo in the primary endpoint – the change from baseline in the total score on the Positive and Negative Syndrome Scale (PANSS) as well as on multiple secondary endpoints.

The percentage of patients who had a 50% or greater reduction in PANSS score were: placebo 29%, brexpiprazole 1 mg/day 42%, brexpiprazole 2 mg/day 37%, brexpiprazole 4 mg/day 48%. The drug-placebo difference for the 1 mg/day and 4 mg/day groups was statistically significantly different than placebo. The magnitude of the difference was 12.5% for the 1 mg/day dose and 18.7% for the 4 mg/day dose, both of which are clinically meaningful.

Patients who received brexpiprazole 1 mg/day and 2 mg/day did not show statistically significantly greater improvement than patients who received placebo.

Adverse events that occurred in at least 5% of patients on any of the doses of brexpiprazole and at least twice as often as on placebo (the usual definition of “common adverse events”): None!

Weight gain? An increase in body weight of 7% or more is usually considered a significant weight gain. It occurred in 4% of patients on placebo, 12% of patients on 2 mg/day of brexpiprazole, and in 11% of those on 4 mg/day of brexpiprazole. More patients on brexpiprazole than on placebo spontaneously reported weight gain as an adverse event.

Sedation occurred in 1% on placebo, 3% on both 3 mg/day and 4 mg/day of brexpiprazole.

Potentially clinically significant increase in creatinine phosphokinase (CPK) levels were predefined as ≥ 3 times the upper limit of normal. Such levels occurred in 4% of those on placebo, 10% of those on brexpiprazole 2 mg/day, and 8% of those on brexpiprazole 4 mg/day.

Clinical Commentary

The two studies above demonstrate that brexpiprazole is efficacious in the treatment of acute exacerbations of schizophrenia at a dose of 4 mg/day and perhaps at 2 mg/day.

An incidence of akathisia less than that with placebo was a striking finding. However, taking all the studies of brexpiprazole into consideration, the incidence of akathisia with brexpiprazole is low but not absent. Akathisia being an important and troublesome adverse effect, at this time, the low incidence of akathisia seems to an important finding in favor of brexpiprazole. Future head-to-head studies comparing brexpiprazole to aripiprazole directly and with comparable dosing and titration schedules will be helpful. Such studies could provide more definitive assessment of whether, in fact, the incidence of akathisia with brexpiprazole is significantly less than with aripiprazole.

Brexpiprazole is, however, not devoid of potential to cause clinically significant weight gain. While the 11 to 12% incidence of clinically significant weight gain may appear to be relatively small, we must keep in mind that this is weight gain over only 6 weeks. It is possible that the incidence of clinically significant weight gain would increase over longer periods of treatment. The Prescribing Information notes that, “In the long-term, open label schizophrenia studies, 20% of patients demonstrated a ≥7% increase in body weight and 10% demonstrated a ≥7% decrease in body weight.” Similarly, it notes that, “In the long-term, open label depression studies, 30% of patients demonstrated a ≥7% increase in body weight and 4% demonstrated a ≥7% decrease in body weight.”

There is increasing recognition of the high prevalence of attention deficit hyperactivity disorder (ADHD) in adults.

Executive dysfunction is a prominent feature of adult ADHD and is more disabling than inattention and hyperactivity in these patients.

However, medications for ADHD appear to have limited benefit in improving executive dysfunction in adult ADHD.

Background

This study aimed to evaluate the effect of atomoxetine on executive functions in young adults with ADHD.

Methods

This was a multi-center, randomized, double-blind, placebo-controlled trial.

Young adults (18 to 30 years old) with ADHD were included in the study.

Patients were randomized to receive atomoxetine (flexible dose 40 to 100 mg/day in two divided doses) or placebo for 12 weeks. In this analysis, 161 patients on atomoxetine and 167 patients on placebo are included.

The main measure of executive functioning was the Behavior Rating Inventory of Executive Function-Adult (BRIEF-A). This patient-reported questionnaire is widely used as a measure of executive dysfunction in clinical trials. It consists of 75 items that measure various aspects of executive functioning.

Results

Patients who received atomoxetine had a statistically significantly greater reduction than those who received placebo on the BRIEF-A Global Executive Composite (GEC) score, Behavioral Regulation Index (BRI) score, and Metacognitive Index (MI) score.

BRIEF-A has nine subscales. On 5 of them, patients who received atomoxetine had statistically significantly greater improvement: Inhibit, Self-Monitor, Working Memory, Plan/Organize, and Task Monitor.

On three BRIEF-A subscales, there was a “trend” towards statistical significantly greater improvement in patients who received atomoxetine: Initiate (p = .051), Organization of Materials (p = .051), and Shift (p = .090).

On the remaining (ninth) subscale, Emotional Control, there was no statistically significant difference between patients who received atomoxetine versus placebo.

Conclusions

Atomoxetine is efficacious for improving executive function in young adults with ADHD.

Limitation: neuropsychological assessment of executive function was not done.

Clinical Commentary

Those of us who treat adult ADHD should focus our attention (pun intended) on assessing and managing executive dysfunction since in adults that is what causes the greatest impairment.

In my opinion, it is the patient report of impairment in day-to-day functioning that is more important than how patients do on neuropsychological tests.

In the past 50 years, there has been a decline in average sleep duration and quality in the general population.

90% of adults in the United States use some type of electronics within one hour before bedtime at least a few nights per week.

Electronic devices may have a negative impact on sleep, possibly due to the short-wavelength-enriched light emitted by these electronic devices.

There has been little research on the potential negative effects of light-emitting e-book readers like an iPadTMon sleep.

Background

The study aimed to compare the biological effects of reading an electronic book on a light-emitting e-book reader versus reading a printed book in the hours before bedtime.

Methods

Twelve healthy young adults (mean age 25 years) were recruited.

The subjects were evaluated over a 14-day inpatient stay.

Subjects read books in two different forms, one for five consecutive evenings and then the other for five consecutive evenings. The two forms were a light-emitting e-book reader (i.e., reading a book on a iPadTM) or a printed book. In both cases, subjects read in very dim room light for about four hours before bedtime and for five consecutive evenings. The books were required to be leisure reading and were chosen by the subjects.

Note: the iPadTM was put on its brightest setting.

A randomized, crossover design was used. That is, the same subjects did one kind of reading in the first few days and then crossed over to doing the other part of the study. However, the subjects were randomized as to which of the two types of reading they would do first.

Evaluations included subject ratings, collection of blood samples, and polysomnography through electroencephalograph electrodes.

The experimental setting was rigorously standardized including use of light sensors, fixing the distance between the subjects and the light-emitting e-book reader, etc.

Results

Compared to subjects who read a printed book, subjects who read on the iPadTM showed the following negative effects:

Evening levels of melatonin were suppressed by about 55% in subjects using the light-emitting e-book reader while there was no suppression in those using print books.

Dim light melatonin onset is a measure of the circadian rhythm and was assessed by measuring hourly plasma melatonin levels using an indwelling catheter. Dim light melatonin onset occurred more than 1.5 hours later on the day following use of a light-emitting e-book reader than after using a print book.

Conclusions

Evening exposure to a light-emitting e-book reader has adverse effects on sleep and circadian rhythm.

Clinical Commentary

The level of detail and the precision of this study were impressive.

There are probably some ways in which we can reduce the negative effects on sleep of using light-emitting electronic devices close to bedtime. For example, reducing the brightness of the device to the minimum necessary, ending the use of the device at least one hour prior to bedtime, etc. In addition, a commentator on this paper noted that the impact of the light one receives at night is moderated by the amount of light one receives during the daytime. Therefore, exposure to plenty of bright light during the day may reduce the impact of using electronic devices in the evening.

However, pending more research into this, it behooves us to should specifically instruct our patients who have problems with sleep or fatigue to avoid or minimize use of light-emitting electronic devices like computers, tablets, and smart phones in the hours immediately before bedtime.

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